The present invention relates to tricyclic compounds having very satisfactory prostaglandin I2 receptor agonistic activity, their production, intermediates and use.
It is known that prostaglandin I2 (PGI2) is a substance which is biosynthesized from arachidonic acid through prostaglandin H2 (PGH2) and has potent platelet aggregation inhibitory activity, vasodilative activity, lipid deposition inhibitory activity, and leukocyte activation inhibitory activity. As such, PGI2 is considered to be effective in the treatment of peripheral vascular diseases (e.g. peripheral embolism, vibration syndrome, Raynaud""s disease, etc.), systemic lupus erythematosus, post-PTCA (percutaneous transluminal coronary angioplasty) arterial reobliteration/restenosis, atherosclerosis, thrombosis, diabetic neuropathy, hypertension, ischemic diseases (e.g. cerebral infarction, myocardial infarction, etc.), transient ischemic attack, and glomerulonephritis.
Meanwhile, WO 96/20925, for instance, reports a non-prostanoid PGI2 receptor agonist compound of the formula: 
wherein R1 represents xe2x80x94Xxe2x80x94(CH2)nCOOR3 wherein X represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH2xe2x80x94; R3 typically represents hydrogen or C1-5 lower alkyl; n represents 1-3; R2 typically represents xe2x80x94CR4xe2x95x90CR5xe2x80x94Oxe2x80x94 or xe2x80x94CR5xe2x95x90CR4xe2x80x94Oxe2x80x94 wherein R4 represents xe2x80x94(CH2)mxe2x80x94Yxe2x80x94R8 wherein m represents 1-4; Y typically represents xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94; R8 typically represents phenyl; R5 typically represents hydrogen or C1-5 lower alkyl.
JP-A-62-252780 discloses an antiulcer tricyclic compound of the formula: 
wherein X and Y independently represent hydrogen, halogen, lower alkyl or lower alkoxy; n represents 0-4; R1 represents hydrogen, lower alkyl, unsubstituted or substituted phenyl; R2 typically represents lower alkyl, unsubstituted or substituted phenyl, heterocyclic group or cyclic amino; R3 represents hydrogen, lower alkyl, or acyl; R2 and R3 optionally taken together represent cyclic amino.
PGI2 is by no means chemically and biologically stable enough for use as a medicine. Moreover, it is not clear-cut in the desired action or actions versus other actions, thus unavoidably inducing adverse drug reactions.
Meanwhile, no information is available on the relation of those known tricyclic compounds to the affinity for PGI2 receptors. Under the circumstances, there is a keen demand for creation of a compound structurally removed from PGI2 and yet having a high affinity for PGI2 receptors and acting as a PGI2 receptor agonist with improved chemical stability and stability against metabolism and greater clinical efficacy than PGI2, thus being very satisfactory for use as a medicine.
The inventors of the present invention explored for compounds having PGI2 receptor agonistic activity and succeeded in the creation of a compound of the formula: 
wherein
R1 represents hydrogen or a substituent group;
m represents an integer of 1 to 3;
Ar represents an aromatic group which may be substituted;
X represents a bond or a divalent straight-chain group which have 1 to 6 atoms and may be substituted;
Y represents xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R2)xe2x80x94 wherein R2 represents hydrogen or a substituent group;
Z represents xe2x80x94Nxe2x95x90 or xe2x80x94C(R3)xe2x95x90 wherein R3 represents hydrogen or a hydrocarbon group;
ring A represents a benzene ring which may be substituted by a substituent in addition to a group of the formula:
xe2x80x94O(CH2)mCOR1 
xe2x80x83wherein the respective symbols have the same meanings as defined above; and
ring B represents a 5- to 7-membered ring which may be substituted, or a salt thereof,
which compound is structurally characterized in that the benzene ring (ring A) of the tricyclic skeletal system of the formula: 
wherein the respective symbols have the meanings defined above, has a substituent group of the formula xe2x80x94O(CH2)mCOR1 wherein the respective symbols have the meanings defined above.
The inventors further discovered that because of the above unique chemical structure, the above compound or a salt thereof [hereinafter sometimes referred to briefly as compound (I)], is an excellent PGI2 receptor agonist having a high affinity for PGI2 receptors, high chemical stability, and high stability against metabolism and, thus, being fully satisfactory as a medicine. The present invention is predicated on the above findings.
The present invention to:
(1) compound (I);
(2) a compound of the above (1) wherein
R1 is
(i) hydrogen,
(ii) a hydroxy which may be substituted by a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-6 alkyl which may be halogenated, C2-6 alkenyl which may be halogenated, C2-6 alkynyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C6-10 aryl, C7-11 aralkyl, C1-6 alkoxy which may be halogenated, C6-10 aryloxy, C1-6 alkyl-carbonyl, C6-10 aryl-carbonyl, C7-11 aralkyl-carbonyl, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 3- to 6-membered cyclic amino, C1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C1-6 alkylthio which may be halogenated, C6-10 arylthio, C1-6 alkylsulfinyl, C6-10 arylsulfinyl, C1-6 alkylsulfonyl and C6-10 arylsulfonyl, or
(iii) an amino which may be substituted by 1 or 2 substituents selected form the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl and C7-16 aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-6 alkyl which may be halogenated, C2-6 alkenyl which may be halogenated, C2-6 alkynyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C6-10 aryl, C7-11 aralkyl, C1-6 alkoxy which may be halogenated, C6-10 aryloxy, C1-6 alkyl-carbonyl, C6-10 aryl-carbonyl, C7-11 aralkyl-carbonyl, C1-6 alkyl-carbonyloxy, C6-10 aryl-carbonyloxy, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, 3- to 6-membered cyclic amino, C1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C1-6 alkylthio which may be halogenated, C6-10 arylthio, C1-6 alkylsulfinyl, C6-10 arylsulfinyl, C1-6 alkylsulfonyl and C6-10 arylsulfonyl;
m is an integer of 1 to 3;
Ar is a
(i) C6-14 aryl or
(ii) 5- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from among nitrogen, sulfur and oxygen as a ring member other than carbon, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkylcarbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy;
X is
(i) a bond or
(ii) a divalent group of the formula:
xe2x80x94Xaxe2x80x94Xbxe2x80x94
xe2x80x83wherein Xa is a bond, S, SO, SO2, O or NR4, wherein R4 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-14 aryl, C7-11 aralkyl, formyl, C1-6 alkyl-carbonyl or C6-10 aryl-carbonyl; and
Xb is (a) a bond or (b) C1-5 alkylene, C2-5 alkenylene, C2-5 alkynylene or a group of the formula:
xe2x80x94(CH2)pxe2x80x94Xcxe2x80x94(CH2)qxe2x80x94 
xe2x80x83wherein Xc is S, SO, SO2, O or NR4a, wherein R4a is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-14 aryl, C7-11 aralkyl, formyl, C1-6 alkyl-carbonyl or C6-10 aryl-carbonyl; p and q are independently an integer of 0 to 4 and p+q is an integer of 0 to 4, each of which group may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) nitro, (3) cyano, (4) C1-6 alkyl which may be halogenated, (5) C3-6 cycloalkyl, (6) C7-11 aralkyl, (7) C1-6 alkoxy which may be halogenated, (8) C1-6 alkylthio which may be halogenated, (9) hydroxy, (10) amino, (11) mono-C1-6 alkylamino, (12) di-C1-6 alkylamino, (13) C6-10 aryloxy, (14) C1-6 alkyl-carbonyl, (15) C6-10 aryl-carbonyl, (16) oxo and (17) a (17-i) C6-14 aryl or (17-ii) 5- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from among nitrogen, sulfur and oxygen as a ring member other than carbon, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkyl-carbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy;
R2 is (i) hydrogen, (ii) C1-6 alkyl, (iii) C2-6 alkenyl, (iv) C2-6 alkynyl, (v) C3-6 cycloalkyl, (vi) C6-14 aryl, (vii) C7-16 aralkyl, (viii) formyl, (ix) C1-6 alkyl-carbonyl, (x) C6-10 aryl-carbonyl, (xi) C7-11 aralkyl-carbonyl, (xii) C1-6 alkylsulfonyl, (xiii) C6-10 arylsulfonyl which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and nitro or (xiv) C7-11 aralkylsulfonyl;
R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl;
ring A is a benzene ring which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkyl-carbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy, in addition to a group of the formula:
xe2x80x94O(CH2)mCOR1; 
xe2x80x83and
ring B is a 5- to 7-membered ring of the formula: 
xe2x80x83wherein Ba is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94S(O)rxe2x80x94, S(O)rxe2x80x94CH2xe2x80x94, or xe2x80x94S(O)rxe2x80x94(CH2)2xe2x80x94 wherein r is an integer of 0 to 2, which ring may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl and C7-16 aralkyl;
(3) a compound of the above (1) wherein the group of the formula: xe2x80x94COR1 is carboxy which may be esterified or amidated;
(4) a compound of the above (1) wherein R1 is hydroxy which may be substituted;
(5) a compound of the above (1) wherein R1 is hydroxy;
(6) a compound of the above (1) wherein m is 1;
(7) a compound of the above (1) wherein Ar is a C6-14 aryl which may be substituted by 1 to 3 substituents selected form the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkyl-carbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy;
(8) a compound of the above (1) wherein Ar is phenyl which may be halogenated;
(9) a compound of the above (1) wherein X is a divalent group of the formula:
xe2x80x94Xa1xe2x80x94Xb1xe2x80x94 
xe2x80x83wherein Xa1 is S, SO or SO2; and Xb1 is C1-5 alkylene which may be substituted by a C6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkyl-carbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy;
(10) a compound of the above (9) wherein Xa1 is S;
(11) a compound of the above (9) wherein Xb1 is a C1-3 alkylene which may be substituted by a phenyl which may be halogenated;
(12) a compound of the above (1) wherein Y is xe2x80x94Sxe2x80x94;
(13) a compound of the above (1) wherein Z is xe2x80x94Nxe2x95x90;
(14) a compound of the above (1) wherein ring B is a ring of the formula: 
xe2x80x83wherein Ba1 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
(15) a compound of the above (1) which is a compound of the formula: 
xe2x80x83wherein the respective symbols have the same meanings as defined above;
(16) a compound of the above (15) wherein
R1 is hydroxy;
m is 1;
Ar is phenyl which may be halogenated;
X is a divalent group of the formula:
xe2x80x94Xa2xe2x80x94Xb2xe2x80x94 
xe2x80x83wherein Xa2 is S, SO or SO2; and Xb2 is a C1-3 alkylene which may be substituted by a phenyl which may be halogenated; and
ring B is a ring of the formula: 
xe2x80x83wherein Ba2 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
(17) a compound of the above (1) wherein
R1 is hydroxy which may be substituted by a C1-6 alkyl;
m is an integer of 1 to 3;
Ar is C6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, C1-6 alkyl which may be halogenated, C1-6 alkoxy and C6-10 aryl;
X is
(i) a bond or
(ii) a divalent group of the formula:
xe2x80x94Xa3xe2x80x94Xb3xe2x80x94 
wherein Xa3 is a bond, S, SO, SO2, O or NH; and
Xb3 is a C1-5 alkylene or C2-5 alkenylene group which may be substituted by a phenyl which may be halogenated;
Y is xe2x80x94Sxe2x80x94;
Z is xe2x80x94Nxe2x95x90;
ring A is a benzene ring which may be substituted by 1 to 3 C1-6 alkyl, in addition to a group of the formula:
xe2x80x94O(CH2)mCOR1; 
xe2x80x83and
ring B is a ring of the formula: 
xe2x80x83wherein Ba3 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94;
(18) a compound of the above (1) which is
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid, or a salt thereof;
(19) a compound of the above (1) which is
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid, or a pharmaceutically acceptable metal salt;
(20) a process for producing a compound of the above (1) which comprises
i) reacting a compound of the formula: 
xe2x80x83wherein Hal represents halogen; the other symbols have the same meanings as defined above, or a salt thereof with a compound of the formula: 
xe2x80x83wherein the respective symbols have the same meanings as defined above, or a salt thereof, optionally followed by hydrolysis or oxidation of the resultant compound; or
ii) subjecting a compound of the formula: 
xe2x80x83wherein Xxe2x80x2 represents SH, OH or NH2; the other symbols have the same meanings as defined above, or a tautomer thereof, or a salt thereof, to alkylation, optionally followed by hydrolysis or oxidation of the resultant compound;
(21) a compound of the formula: 
xe2x80x83wherein Xxe2x80x2 represents SH, OH, or NH2; the other symbols have the same meanings as defined above or a tautomer thereof, or a salt thereof;
(22) a pharmaceutical composition which comprises a compound of the above (1), if necessary together with a pharmaceutically acceptable carrier;
(23) a composition of the above (22) which is for eliciting a prostaglandin I2 receptor agonistic effect;
(24) a composition of the above (22) which is for inhibiting a platelet aggregation;
(25) a composition of the above (22) which is for the prophylaxis or treatment of transient ischemic attack, diabetic neuropathy, peripheral vascular diseases or ulcer;
(26) a method for eliciting a prostaglandin I2 receptor agonistic effect in a mammal in need thereof which comprises administering to such mammal an effective amount of a compound of the above (1) with a pharmaceutically acceptable excipient, carrier or diluent; and
(27) use of a compound of the above (1) for manufacturing a pharmaceutical composition for eliciting a prostaglandin I2 receptor agonistic effect.
Referring to the above formula, the xe2x80x9csubstituent groupxe2x80x9d represented by R1 includes, for example, a hydroxy which may be substituted and an amino which may be substituted.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9chydroxy which may be substitutedxe2x80x9d and for the xe2x80x9camino which may be substitutedxe2x80x9d includes, for example, hydrocarbon groups which may be substituted. The xe2x80x9camino which may be substitutedxe2x80x9d may have 1 or 2 substituent groups.
The xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d means a monovalent group available upon elimination of one hydrogen atom from a hydrocarbon compound and includes both acyclic and cyclic hydrocarbon groups (e.g. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc.). Preferred are acyclic and cyclic hydrocarbon groups containing 1 to 16 carbon atoms, such as the following.
a) C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
b) C2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, etc.),
c) C2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl, etc.),
d) C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
e) C6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, 2-anthryl, etc.),
f) C7-16 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.), preferably benzyl.
Among the above hydrocarbon groups, C1-6 alkyl, C6-14 aryl, and C7-16 aralkyl are preferred.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl which may be halogenated, C2-6 alkenyl which may be halogenated, C2-6 alkynyl which may be halogenated, C3-6 cycloalkyl which may be halogenated, C6-10 aryl (e.g. phenyl, naphthyl, etc.), C7-11 aralkyl (e.g. benzyl, xcex1-methylbenzyl, phenethyl, etc.), C1-6 alkoxy which may be halogenated, C6-10 aryloxy (e.g. phenoxy etc.), C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C6-10 aryl-carbonyl (e.g. benzoyl, naphthoyl, etc.), C7-11 aralkyl-carbonyl (e.g. benzylcarbonyl, phenethylcarbonyl, etc.), C1-6 alkylcarbonyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), C6-10 aryl-carbonyloxy (e.g. benzoyloxy, naphthoyloxy, etc.), carboxy, C1-6 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), carbamoyl, mono-C1-6 alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkylcarbamoyl, (e.g. dimethylcarbamoyl, diethylcarbamoyl, etc.), amidino, imino, amino, mono-C1-6 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g. dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), 3- to 6-membered cyclic amino which may contain 1 to 3 hetero atoms selected from among oxygen, sulfur and nitrogen as ring members in addition to carbon and one nitrogen atom (e.g. aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, thiomorpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), C1-3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.), hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C1-6 alkylsulfamoyl (e.g. methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl, etc.), di-C1-6 alkylsulfamoyl (e.g. dimethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, dibutylsulfamoyl, etc.), C1-6 alkylthio which may be halogenated, C6-10 arylthio (e.g. phenylthio, naphthylthio, etc.), C1-6 alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), C6-10 arylsulfinyl (e.g. phenylsulfinyl, naphthylsulfinyl, etc.), C1-6 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), and C6-10 arylsulfonyl (e.g. phenylsulfonyl, naphthylsulfonyl, etc.).
The above-mentioned xe2x80x9cC1-6 alkyl which may be halogenatedxe2x80x9d includes, for example, C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Specifically, mention may be made of methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
The xe2x80x9cC2-6 alkenyl which may be halogenatedxe2x80x9d includes, for example, C2-6 alkenyl (e.g. vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
The xe2x80x9cC2-6 alkynyl which may be halogenatedxe2x80x9d includes, for example, C2-6 alkynyl (e.g. 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
The xe2x80x9cC3-6 cycloalkyl which may be halogenatedxe2x80x9d includes, for example, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Specifically, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.
The xe2x80x9cC1-6 alkoxy which may be halogenatedxe2x80x9d includes, for example, C1-6 alkoxy optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Specifically, mention may be made of methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
The xe2x80x9cC1-6 alkylthio which may be halogenatedxe2x80x9d includes, for example, C1-6 alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Specifically, mention may be made of methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.
The above-mentioned xe2x80x9chydrocarbon groupxe2x80x9d may have 1 to 5, preferably 1 to 3, substituents selected from the group consisting of the above-mentioned substituents in its substitutable position or positions and when 2 or more substitutions are involved, the substituents may be the same group or different groups.
The formula:
xe2x80x94COR1 
preferably represents carboxy which may be esterified or amidated.
R1 preferably represents hydroxy which may be substituted. More preferably is hydroxy.
Preferably, m is 1.
The xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d as mentioned for Ar includes, for example, aromatic hydrocarbon groups and aromatic heterocyclic (heteroaromatic) groups.
The xe2x80x9caromatic hydrocarbon groupxe2x80x9d mentioned above includes, for example, monocyclic or fused polycyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specifically, C6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, etc. can be mentioned. Preferred is phenyl, 1-naphthyl or 2-naphthyl. Particularly preferred is phenyl.
The xe2x80x9caromatic heteocyclic groupxe2x80x9d mentioned above includes, for example, 5- to 10-mentioned monocyclic or its fused heteroaromatic groups containing one or more, for example 1 to 4, hetero atoms selected from among nitrogen, sulfur and oxygen as a ring member other than carbon. Specifically, it includes monovalent groups available upon elimination of any one hydrogen atom each from 5- or 6-membered monocyclic heteroaromatic rings or fused ring systems consisting of any such heteroaromatic ring and 1 or 2 (preferably 1) aromatic rings (e.g. benzene ring, pyridine ring, etc.), such as thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, triazine, 1,2,3-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, etc. Preferred examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include 5- to 10-membered heteroaromatic groups such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzythienyl, benzofuranyl, 2-thienyl, 3-thienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl, etc. More preferred are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, etc. Those heteroaromatic groups may be in the N-oxide form, where applicable.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9caromatic group which may be substitutedxe2x80x9d as mentioned for Ar includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.), nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g. dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, etc.), C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.), carboxy, C1-6 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl, mono-C1-6 alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl, etc.), C6-10 aryl-carbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl, etc.), sulfo, C1-6 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.), C6-10 aryl (e.g. phenyl, naphthyl, etc.), and C6-10 aryloxy (e.g. phenyloxy, naphthyloxy, etc.). When the substituent is C1-3 alkylenedioxy, it preferably forms a ring in combination with the two adjacent carbon atoms.
The above-mentioned xe2x80x9cC1-6 alkyl which may be halogenatedxe2x80x9d, xe2x80x9cC1-6 alkoxy which may be halogenatedxe2x80x9d, and xe2x80x9cC1-6 alkylthio which may be halogenatedxe2x80x9d may be the same groups as those respectively mentioned above in the definition of xe2x80x9cthe substituentxe2x80x9d for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
The xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group which may be substitutedxe2x80x9d may have 1 to 5, preferably 1 to 3, substituents as selected from among the above-mentioned substituents in its substitutable position or positions of the aromatic ring and where two or more substitutions are involved, the substituents group may be the same group or different groups.
Preferably, Ar is C6-14 aryl which may be substituted, etc. More preferably, Ar is phenyl which may be halogenated.
The xe2x80x9cdivalent straight-chain group which have 1 to 6 atoms and may be substitutedxe2x80x9d as mentioned for X includes, for example, divalent groups of the formula:
xe2x80x94Xaxe2x80x94Xbxe2x80x94 
wherein Xa represents a bond, S, SO, SO2, O, or NR4; Xb represents a bond or a divalent aliphatic hydrocarbon group having 1 to 5 atoms (preferably 1 to 4 atoms) which may be substituted and may contain oxygen, nitrogen, or sulfur. In the above formula, R4 represents hydrogen, C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, etc.), C6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.), C7-11 aralkyl (e.g. benzyl, phenethyl, etc.), formyl, C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), or C6-10 aryl-carbonyl (e.g. benzoyl, naphthoyl, etc.), for instance.
Xa is preferably a bond, S, SO, SO2, O, or NH. More preferred is S, SO, SO2, O, or NH. Particularly preferred is S, SO or SO2. Most preferably, Xa is S.
The xe2x80x9cdivalent aliphatic hydrocarbon group having 1 to 5 atoms which may contain sulfur, oxygen, or nitrogenxe2x80x9d of the xe2x80x9cdivalent aliphatic hydrocarbon group having 1 to 5 atoms which may be substituted and may contain sulfur, oxygen, or nitrogenxe2x80x9d as mentioned for Xb means a divalent aliphatic hydrocarbon group having 1 to 5 atoms which is available upon elimination of two hydrogen atoms from a saturated or an unsaturated aliphatic hydrocarbon and optionally containing 1 or 2 (preferably 1) sulfur, oxygen, or nitrogen atom between carbon atoms or in its terminal position.
Specifically, the examples include
(i) C1-5 alkylene (e.g. xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, etc.)
(ii) C2-5 alkenylene (e.g. xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc.)
(iii) C2-5 alkynylene (e.g. xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, etc.)
(iv) groups of the formula:
xe2x80x94(CH2)pxe2x80x94Xcxe2x80x94(CH2)qxe2x80x94 
xe2x80x83wherein Xc represents S, SO, SO2, O, or NR4a; p and q independently represent an integer of 0 to 4 and p+q is an integer of 0 to 4. R4a- in this formula includes the same groups as those mentioned for R4.
The above-mentioned xe2x80x9cdivalent aliphatic hydrocarbon group having 1 to 5 atoms which may contain sulfur, oxygen, or nitrogenxe2x80x9d is preferably C1-5 alkylene or C2-5 alkenylene. Particularly preferred is methylene.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cdivalent straight-chain group which have 1 to 6 atoms and may be substitutedxe2x80x9d or for the xe2x80x9cdivalent aliphatic hydrocarbon group having 1 to 5 atoms which may be substituted and may contain sulfur, oxygen, or nitrogenxe2x80x9d includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C7-11 aralkyl (e.g. benzyl, phenethyl, etc.), C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C1-6 alkylamino (e.g. dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, etc.), C6-10 aryloxy (e.g. phenyloxy, naphthyloxy, etc.), C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C6-10 aryl-carbonyl (e.g. benzoyl, naphthoyl, etc.), oxo, and aromatic groups which may be substituted.
The above-mentioned xe2x80x9cC1-6 alkyl which may be halogenatedxe2x80x9d, xe2x80x9cC1-6 alkoxy which may be halogenatedxe2x80x9d, and xe2x80x9cC1-6 alkylthio which may be halogenatedxe2x80x9d include those specific groups as respectively mentioned as the substituent for the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
The above-mentioned xe2x80x9caromatic group which may be substitutedxe2x80x9d includes the same groups as those mentioned for the xe2x80x9caromatic group which may be substitutedxe2x80x9d for Ar.
Among those substituents, halogen, hydroxy, and an aromatic group which may be substituted are preferred. Particularly preferred is C6-14 aryl.
Those substituents may occur in 1 to 5, preferably 1 to 3, substitutable positions and where two or more substitutions are involved, the substituents may be the same group or different groups.
Xb is preferably (i) a bond, (ii) C1-5 alkylene which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy and an aromatic group which may be substituted, or (iii) C2-5 alkenylene which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy and an aromatic group which may be substituted. Preferred examples of the above xe2x80x9caromatic group which may be substitutedxe2x80x9d are C6-14 aryl or 5- to 10-membered aromatic heterocyclic group each containing 1 to 4 hetero atoms selected from among nitrogen, sulfur, and oxygen as ring members in addition to carbon, each of which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy and hydroxy.
It is also preferable that this xe2x80x9caromatic group which may be substitutedxe2x80x9d be present on the carbon atom in the terminal position where Ar is attached.
More preferably, Xb is (i) a bond or (ii) a C1-5 alkylene which may be substituted by an aromatic group (preferably C6-14 aryl) which may be substituted. Particularly preferred is a C1-5 alkylene which may be substituted by a C6-14 aryl which may be substituted. Most preferred is a C1-3 alkylene which may be substituted by a phenyl which may be halogenated.
X is preferably a divalent group of the formula:
xe2x80x94Xa1xe2x80x94Xb1xe2x80x94
wherein Xa1 is S, SO or SO2; and Xb1 is C1-5 alkylene which may be substituted by a C6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl which may be halogenated, C3-6 cycloalkyl, C1-6 alkoxy which may be halogenated, C1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkyl-carbonyl, carboxy, C1-6 alkoxy-carbonyl, carbamoyl, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, sulfo, C1-6 alkylsulfonyl, C6-10 aryl and C6-10 aryloxy. Xa1 is preferably S. Xb1 is preferably C1-3 alkylene which may be substituted by a phenyl which may be halogenated.
R2 in xe2x80x94N(R2)xe2x80x94 for Y represents hydrogen or a substituent group and this xe2x80x9csubstituent groupxe2x80x9d may for example be a hydrocarbon group or an acyl.
The above-mentioned xe2x80x9chydrocarbon groupxe2x80x9d includes the same hydrocarbon group as the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
The above-mentioned xe2x80x9cacylxe2x80x9d may for example be an acyl derived from a carboxylic acid or a sulfonic acid. Preferred examples are formyl, C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C6-10 aryl-carbonyl (e.g. benzoyl, naphthoyl, etc.), C7-11 aralkyl-carbonyl (e.g. benzylcarbonyl, phenethylcarbonyl, naphthylmethylcarbonyl, etc.), C1-6 alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, etc.), C6-10 arylsulfonyl which may be substituted, and C7-11 aralkylsulfonyl (e.g. benzylsulfonyl, phenethylsulfonyl, naphthylmethylsulfonyl, etc.).
The xe2x80x9cC6-10 arylsulfonylxe2x80x9d of the above-mentioned xe2x80x9cC6-10 arylsulfonyl which may be substitutedxe2x80x9d includes, for example, phenylsulfonyl and naphthylsulfonyl. The xe2x80x9csubstituentxe2x80x9d for this xe2x80x9cC6-10 arylsulfonyl which may be substitutedxe2x80x9d includes, for example, C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), and nitro. The xe2x80x9cC6-10 arylsulfonylxe2x80x9d of the xe2x80x9cC6-10 arylsulfonyl which may be substitutedxe2x80x9d may have 1 to 3 substituents selected from among the substituents mentioned above and where two or more substituents are present, they may be the same group or different groups. Specific examples are tosyl and m-nitrobenzenesulfonyl.
R2 is preferably hydrogen.
Y is preferably xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94. More preferred is xe2x80x94Sxe2x80x94.
R3 in xe2x80x94C(R3)xe2x95x90 for Z represents hydrogen or a hydrocarbon group. The xe2x80x9chydrocarbon groupxe2x80x9d includes the same hydrocarbon group as the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
R3 is preferably hydrogen.
Z is preferably xe2x80x94Nxe2x95x90.
The xe2x80x9csubstituentxe2x80x9d for the xe2x80x9cbenzene ring which may be substituted by a substituent, in addition to a group of the formula:
xe2x80x94O(CH2)mCOR1 
(wherein the respective symbols have the same meanings as defined above)xe2x80x9d as mentioned for ring A may number 1 to 3 and includes the same groups as the substituents mentioned for the xe2x80x9caromatic group which may be substitutedxe2x80x9d for Ar. Where two or more substitutions are involved, the substituents may be the same group or different groups.
The xe2x80x9c5- to 7-membered ringxe2x80x9d of the xe2x80x9c5- to 7-membered ring which may be substitutedxe2x80x9d as mentioned for ring B is a 5- to 7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring which may contain 1 to 3 hetero atoms selected from among oxygen, sulfur, and nitrogen (preferably one hetero atom selected from the group consisting of oxygen and sulfur) as ring members in addition to carbon. Among preferred examples of the xe2x80x9c5- to 7-membered ringxe2x80x9d are 5- to 7-membered rings of the formula: 
wherein Ba represents xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94S(O)rxe2x80x94, xe2x80x94S(O)rxe2x80x94CH2xe2x80x94, or xe2x80x94S(O)rxe2x80x94(CH2)2xe2x80x94 wherein r represents an integer of 0 to 2.
Preferably, Ba is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94.
The xe2x80x9csubstituentxe2x80x9d for the above-mentioned xe2x80x9c5 to 7-membered ringxe2x80x9d may for example be a hydrocarbon group. This xe2x80x9chydrocarbon groupxe2x80x9d includes the same hydrocarbon group as mentioned for the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d.
This xe2x80x9c5- to 7-membered ringxe2x80x9d may have 1 to 3 substituents selected from among the above-mentioned substituents in substitutable positions and where two or more substitutions are involved, the substituents may be the same group or different groups.
Among the compounds of formula (I), preferred is the compound of the following formula or a salt thereof. 
wherein the respective symbols have the same meanings as defined above. More preferred is the compound, inclusive of its salt, wherein
R1 is hydroxy;
m is 1;
Ar is phenyl which may be halogenated;
X is a divalent group of the formula:
xe2x80x94Xa2xe2x80x94Xb2xe2x80x94
wherein Xa2 is S, SO or SO2; and Xb2 is C1-3 alkylene which may be substituted by a phenyl which may be halogenated; and
ring B is a ring of the formula: 
wherein Ba2 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94.
In compound (I), the preferred is a compound wherein
R1 is hydroxy which may be substituted by a C1-6 alkyl;
m is an integer an 1 to 3;
Ar is C6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, C1-6 alkyl which may be halogenated, C1-6 alkoxy and C6-10 aryl;
X is
(i) a bond or
(ii) a divalent group of the formula:
xe2x80x94Xa3xe2x80x94Xb3xe2x80x94
xe2x80x83wherein
Xa3 is a bond, S, SO, SO2, O or NH; and
Xb3 is a C1-5 alkylene or C2-5 alkenylene group which may be substituted by a phenyl which may be halogenated;
Y is xe2x80x94Sxe2x80x94;
Z is xe2x80x94Nxe2x95x90;
ring A is a benzene ring which may be substituted by 1 to 3 C1-6 alkyl, in addition to a group of the formula:
xe2x80x94O(CH2)mCOR1; 
xe2x80x83and
ring B is a ring of the formula: 
xe2x80x83wherein Ba3 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94.
The preferred species of compound (I) of the invention include:
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid, and a salt thereof. As the salt, a pharmaceutically acceptable metal salt is preferred.
Depending on the kinds of substituents it possesses, compound (I) gives rise to stereoisomers. Such stereoisomers and mixtures thereof also fall within the scope of the invention.
The salt of compound (I) according to the present invention typically includes various pharmacologically acceptable salts. Examples of the salt include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. The preferred salt with an inorganic base includes, for example, alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., and aluminum salt. The preferred salt with an organic base includes, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. The preferred salt with an inorganic acid includes, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. The preferred salt with an organic acid includes, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. The preferred salt with a basic amino acid includes, for example, salts with arginine, lysine, ornithine, etc. The preferred salt with an acidic amino acid includes, for example, salts with aspartic acid, glutamic acid, etc.
Particularly preferred are pharmaceutically acceptable salts. For example, when the compound (I) contains a basic functional group, the preferred salt includes, for example, salts with such inorganic acids as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. and salts with such organic acids as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. When an acidic functional group is present, for example, alkali metal salts such as sodium salt and potassium salt, etc., alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salts are preferred.
The process for producing the compound (I) of the invention is now described.
Compound (I) of the invention can be produced by the per se known processes or by any processes analogous thereto, for example in accordance with the following reaction schemes (Reaction scheme 1 and Reaction scheme 2). The symbols used for the respective compounds in those schemes have the same meanings as defined above. Compounds (II) to (XIV) in the reaction schemes include their salts. The salts may for example be of the same kind as the salt of compound (I). 
Compound (II) wherein Ra represents a hydrocarbon group; the other symbols have the same meanings as defined above, can be produced by the per se known method, for example the process described in Berichte deutschen chemischen Gesellschaft 58B, 1947 (1925), or by any process analogous thereto.
The xe2x80x9chydrocarbon groupxe2x80x9d mentioned for Ra includes the same hydrocarbon group as those mentioned for the xe2x80x9chydrocarbon groupxe2x80x9d.
Compound (VI) wherein Rb represents a hydrocarbon group, can be produced by the per se known method, for example the process described in Journal of the Chemical Society, 1434 (1951), or by any process analogous thereto.
The xe2x80x9chydrocarbon groupxe2x80x9d mentioned for Rb includes the same hydrocarbon group as those mentioned above for the xe2x80x9chydrocarbon groupxe2x80x9d.
Compound (VII) can be produced by the per se known method, for example the process described in Organic Syntheses, 27, 73 (1947), or by any process analogous thereto.
Compound (IX) may be purchased from a commercial source if it is available on the market or can be produced by the per se known method, for example the process described in Shin Jikken Kagaku Koza (New Series in Experimental Chemistry) 14, III, 1628-1644 (1978).
Compound (III) can be produced by hydrolyzing compound (II) using an acid catalyst. The acid catalyst includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., silicon compounds such as trimethylsilyl iodide (Me3SiI), trimethylsilyl chloride (Me3SiCl), etc., and Lewis acids such as aluminum chloride, boron tribromide, etc. If necessary, an additive as ethanedithiol or sodium iodide may be used in combination with a Lewis acid. The amount of the acid catalyst, taking a mineral acid as an example, is generally about 1 to 100 moles, preferably about 10 to 50 moles, per mole of compound (II), and when a silicon compound or a Lewis acid is used, is generally about 1 to 20 moles, preferably about 1 to 5 moles, per mole of compound (II). The amount of the additive used in combination with a Lewis acid is generally about 0.1 to 20 moles, preferably about 1 to 10 moles, per mole of compound (II).
This reaction can be advantageously carried out in the absence of a solvent or in the presence of a solvent indifferent to the reaction (hereinafter referred to as an inert solvent). There is no particular limitation on the inert solvent that can be used unless the progress of the reaction is interferred with. When a mineral acid is used, for instance, the solvent is preferably water of mixtures of water with organic solvents, for example, alcohols such as methanol, ethanol, propanol, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.
When a silicon compound or a Lewis acid is used, the solvent is preferably saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of these solvents.
The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally xe2x88x9278xc2x0 C. to 200xc2x0 C., preferably xe2x88x9220xc2x0 C. to 150xc2x0 C.
The reaction product can be used, either as the reaction mixture as such or in a partially purified form, in the next reaction. However, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Compound (IV) can be produced by reacting compound (III) with a compound of the formula:
Lxe2x80x94(CH2)mCOR1 
wherein L represents a leaving group; R1 is as defined above, and a salt thereof.
The xe2x80x9cleaving groupxe2x80x9d for L includes, for example, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkylsulfonyloxy (e.g. methanesulfonyloxy, ethanesulfonyloxy, etc.), and C6-10 arylsulfonyloxy which may be substituted. The xe2x80x9cC6-10 arylsulfonyloxy which may be substitutedxe2x80x9d includes, for example, C6-10 arylsulfonyloxy (e.g. phenylsulfonyloxy, naphthylsulfonyloxy, etc.) which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and nitro. Specifically, it includes m-nitrobenzenesulfonyloxy and p-toluenesulfonyloxy, among other.
The base includes, for example, inorganic bases, e.g. alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., alkali metal hydrides such as sodium hydride, potassium hydride, etc., metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The amount of the base is generally about 0.5 to 5 moles, preferably about 1 to 3 moles, per mole of compound (III).
The proportion of the compound of the formula:
Lxe2x80x94(CH2)mCORxe2x80x2 
wherein the respective symbols have same meanings as defined above, is about 0.8 to 2 moles, preferably about 1 to 1.5 moles, per mole of compound (III).
This reaction can be carried out with advantage in an inert solvent. Among such solvents are alcohols such as methanol, ethanol, propanol, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., ketones such as acetone, methyl ethyl ketone, etc., water, and mixtures of these solvent.
The reaction time is generally 10 minutes to 8 hours, preferably 30 minutes to 3 hours. The reaction temperature is generally 0xc2x0 C. to 120xc2x0 C., preferably 25xc2x0 C. to 100xc2x0 C.
The reaction product can be directly used, either as the reaction mixture as such or in a partially purified form, in the next reaction. If desired, however, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Where R1 in compound (IV) is hydroxy, the compound can be obtained by esterification or ester-exchange reaction in the per se known method using an acid as a catalyst, if desired.
For example, the compound (IV) wherein R1 is hydroxy may be reacted with the corresponding alcohol or ester using an acid as a catalyst. The corresponding alcohol mentioned above includes a compound of the formula:
R1axe2x80x94OH 
wherein R1a represents the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9chydroxy group which may be substitutedxe2x80x9d for above R1. The corresponding ester includes a compound of the formula:
Rxe2x80x94COOR1b 
wherein R represents a hydrocarbon group; and R1b has same meanings as mentioned for R1a.
The xe2x80x9chydrocarbon groupxe2x80x9d mentioned for R includes the same hydrocarbon group as those mentioned for the xe2x80x9chydrocarbon groupxe2x80x9d.
The amount of the corresponding alcohol or ester to be used is about 10 to 1,000 moles per mole of compound (IV).
While the above alcohol or ester is generally expected to serve as the solvent as well, other solvents, for example saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of these solvents can be optionally employed.
The acid catalyst mentioned above includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, etc., and Lewis acids such as boron trifluoride ether complexes. The amount of the acid catalyst to be used is about 0.01 to 2 moles, preferably about 0.1 to 1 mole, per mole of compound (IV).
The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally xe2x88x9210xc2x0 C. to 150xc2x0 C., preferably 50xc2x0 C. to 120xc2x0 C.
The compound (IV) wherein R1 is hydroxy may be reacted with a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, etc.) to give the acid halide (chloride) which can then be reacted with the corresponding alcohol. The corresponding alcohol includes a compound of the formula:
R1axe2x80x94OH 
wherein R1a has same meanings as mentioned above. The proportion of the halogenating agent is generally about 1 to 50 moles, preferably about 1 to 10 moles, per mole of compound (IV). The proportion of the corresponding alcohol is generally about 1 to 5 moles, preferably about 1 to 2 moles, per mole of compound (IV).
This reaction can be carried out with advantage in the absence of a solvent or in the presence of an inert solvent. There is no particular limitation on the kind of inert solvent unless the progress of the reaction is interferred with. The inert solvent includes, for example, esters such as methyl acetate, ethyl acetate, amyl acetate, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of these solvents.
The reaction time is generally 30 minutes to 6 hours, preferably 30 minutes to 2 hours. The reaction temperature is generally xe2x88x9210xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C.
The reaction product can be directly used, either as the reaction mixture as such or in a partially purified form, in the next reaction. If desired, however, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Compound (V) can be produced by reacting compound (IV) with a copper (II) halide (e.g. copper (II) bromide). The proportion of the copper halide is generally about 1 to 3 moles, preferably about 1.5 to 2 moles, per mole of compound (V).
This reaction can be carried out with advantage in an inert solvent. There is no particular limitation on the kind of inert solvent unless the progress of the reaction is interferred with. The inert solvent includes, for example, esters such as methyl acetate, ethyl acetate, amyl acetate, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of these solvents.
The reaction time varies with the species of reagent and solvent used but is generally 1 to 24 hours, preferably 1 to 14 hours. The reaction temperature is generally 0xc2x0 C. to 150xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C.
If desired, compound (V) can also be produced by reacting compound (IV) with a halogen (e.g. bromine, etc.) or a halogenating reagent (e.g. pyridinum hydrobromide perbromide, etc.) optionally in the presence of a base. The proportion of the halogen or the halogenating reagent per mole of compound (IV) is about 1 to 2 moles and preferably about 1 to 1.1 moles. The base that can be used for this purpose includes, for example, inorganic bases, e.g. alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc. and ammonia, organic bases such as triethylamine, pyridine, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The proportion of the base per mole of compound (V) is generally about 0.1 to 5 moles and preferably about 1 to 2 moles.
This reaction can be advantageously carried out in an inert solvent. The solvent is not so critical in kind unless the progress of the reaction is interferred with. The inert solvent includes, for example, alcohols such as methanol, ethanol, propanol, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., organic acids such as formic acid, acetic acid, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of these solvents.
The reaction time is generally 5 minutes to 5 hours, preferably 10 minutes to 1 hour. The reaction temperature is generally xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 60xc2x0 C.
The reaction product can be directly used, either as the reaction mixture as such or in a partially purified form, in the next reaction. If desired, however, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Compound (VIII) can be produced by reacting compound (V) with compound (VI) or compound (VII) optionally in the presence of a base or an acid. The amount of compound (VI) or compound (VII) per mole of compound (V) is generally about 1 to 1.5 moles and preferably about 1 to 1.2 moles. The base that can be used includes inorganic bases such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc., ammonia, etc., organic bases such as triethylamine, pyridine, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The acid that can be used includes carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid, etc. The amount of the base or the acid is generally about 0.1 to 5 moles, preferably about 1 to 2 moles, per mole of compound (V).
This reaction can be conducted with advantage in an inert solvent. The solvent is not so critical in kind unless the progress of the reaction is interferred with. The preferred inert solvent includes, for example, alcohols such as methanol, ethyanol, propanol, etc., ketones such as acetone, methyl ethyl ketone, etc., nitriles such as acetonitrile etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosporic triamide, etc., carboxylic acid such as acetic acid, etc., water, and mixtures of these solvents.
The reaction time varies with the species of reactants and solvent used but is generally 30 minutes to 24 hours, preferably 30 minutes to 14 hours. The reaction temperature is generally 0xc2x0 C. to 150xc2x0 C. and preferably 30xc2x0 C. to 100xc2x0 C.
The reaction product can be directly used, either as the reaction mixture as such or in a partially purified form, in the next reaction. If desired, however, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Compound (I) can be produced by reacting compound (V) with compound (IV) optionally in the presence of an acid or a base. The proportion of compound (IX) per mole of compound (V) is generally about 0.8 to 3 moles and preferably 1 to 1.3 moles. The acid that can be used includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. The base that can be used includes, for example, inorganic bases such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc., ammonia, etc., organic bases such as triethylamine, pyridine, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The amount of the acid or base is about 1 to 1.5 moles, preferably about 1 to 1.3 moles, per mole of compound (V).
This reaction is conducted with advantage in an inert solvent. The inert solvent that can be used includes, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., nitriles such as acetonitrile etc., ketones such as acetone, methyl ethyl ketone, etc., alcohols such as methanol, ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane, 1,2-methoxyethane, diethyl ether, diisopropyl ether, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., trifluoroacetic anhydride, water, and mixtures of these solvents.
The reaction time is generally 30 minutes to 48 hours, preferably 1 to 24 hours. The reaction temperature is generally 0xc2x0 C. to 150xc2x0 C., preferably 25xc2x0 C. to 100xc2x0 C.
Alternatively, compound (I) can be produced by subjecting the Xxe2x80x2 moiety of compound (VIII) to alkylation optionally in the presence of a base. Compound (VIII) may be its tautomer. The tautomer may be a compound of the formula: 
wherein Xxe2x80x3 represents S, O, or NH; the other symbols have the same meanings as defined above.
The alkylation can be carried out in the per se known method. The alkylating agent may for example be a compound of the formula:
Arxe2x80x94Xbxe2x80x94L 
wherein the respective symbols have the same meanings as defined above. The proportion of the alkylating agent is generally about 0.8 to 5 moles, preferably 1 to 2 moles, per mole of compound (VIII).
The base that can be used includes, for example, inorganic bases such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc., organic bases such as triethylamine, pyridine, etc., alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., alkali metal hydrides such as sodium hydride, potassium hydride, etc., metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The proportion of the base is about 1 to 5 moles, preferably about 1 to 1.3 moles, per mole of compound (VIII).
This reaction can be carried out with advantage in an inert solvent. The solvent is not so critical in kind unless the progress of the reaction is interferred with. The preferred inert solvent includes, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., nitriles such as acetonitrile etc., ketones such as acetone, methyl ethyl ketone, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., and mixtures of these solvents.
The reaction time is generally 30 minutes to 12 hours, preferably 1 to 12 hours. The reaction temperature is generally 0xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 80xc2x0 C.
The product compound (I) may be subjected to hydrolysis of its ester bond. This hydrolysis can be carried out in the per se known method and the catalyst that can be used includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., inorganic bases such as sodium hydroxide, potassium hydroxide, etc., and basic salts such as sodium carbonate, potassium carbonate, etc.
This reaction can be carried out with advantage in an inert solvent. The solvent is not particularly critical in kind unless the progress of the reaction is interferred with. The preferred inert solvent includes, for example, alcohols such as methanol, ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., acetic acid, water, and mixtures of these solvents.
The reaction time is generally 10 minutes to 6 hours, preferably 30 minutes to 2 hours. The reaction temperature is generally 0xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 100xc2x0 C. 
Compound (X) wherein Rc represents a hydrocarbon group; the other symbols have the same meanings as defined above, can be produced by the per se known production processes, for example the processes described in Journal of Medicinal Chemistry, 22, 204 (1979), European Journal of Medicinal Chemistry, 23, 31 (1988), and Journal of Heterocyclic Chemistry, 29, 1245 (1992), or by any process analogous thereto.
The xe2x80x9chydrocarbon groupxe2x80x9d for Rc includes the same group as the xe2x80x9chydrocarbon groupxe2x80x9d defined above.
Compound (XI) may be purchased from a commercial source if it is available on the market or can be produced by the per se known, method, for example the process described in Shin Jikken Kagaku Koza (New Series in Experimental Chemistry) 14, II, 1104-1120 (1977).
Compound (XII) can be produced by reacting compound (X) with compound (XI) optionally in the presence of a base. Compound (XI) is used in a proportion of generally about 1 to 5 moles, preferably about 1 to 1.2 moles, per mole of compound (X). The base that can be used includes, for example, inorganic bases such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc., ammonia, etc., organic bases such as triethylamine, pyridine, etc., and basic salts such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, etc. The proportion of the base is generally about 0.1 to 5 moles, preferably about 1 to 2 moles, per mole of compound (X).
This reaction can be carried out with advantage in the absence of a solvent or in the presence of an inert solvent. There is no particular limitation on the kind of inert solvent that can be used unless the progress of the reaction is interferred with. The inert solvent includes, for example, a variety of organic solvents, viz. alcohols such as methanol, ethanol, propanol, etc., saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., water, and mixtures of these solvents.
The reaction time varies with the species of reagents and solvent used but is generally 30 minutes to 24 hours, preferably 2 to 14 hours. The reaction temperature is generally 0xc2x0 C. to 150xc2x0 C., preferably 30xc2x0 C. to 100xc2x0 C.
The product can be directly used, either as the reaction mixture as such or in a partially purified form, in the next reaction. If desired, however, the product compound can be isolated from the reaction mixture in the routine manner and expediently purified by the conventional purification procedure (e.g. recrystallization, distillation, chromatography, etc.).
Compound (XIII) can be produced from compound (XII) by the same procedure as described for the production of compound (III) from compound (II).
Compound (XIV) can be produced from compound (XIII) by the same procedure as described for the production of compound (IV) from compound (III).
Compound (I) can be produced by reacting compound (XIV) with ammonium acetate. The proportion of ammonium acetate is generally about 5 to 100 moles, preferably about 10 to 30 moles, per mole of compound (XIV).
This reaction can be conducted with advantage in the absence of a solvent or in the presence of an inert solvent. The solvent is not critical in kind unless the progress of the reaction is interferred with. The preferred inert solvent includes water or mixtures of water with organic solvents, e.g. organic acids such as acetic acid, propionic acid, etc., alcohols such as methanol, ethanol, propanol, etc., saturated hydorcarbons such as cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl sulfoxide etc., and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.
The reaction time varies with the species of reactant and solvent used by it generally 30 minutes to 24 hours, preferably 2 to 14 hours. The reaction temperature is generally 25xc2x0 C. to 180xc2x0 C., preferably 80xc2x0 C. to 150xc2x0 C.
When the starting compounds for the above reactions have amino, carboxyl, and/or hydroxy groups, such functional groups may have been protected in advance with those protective groups which are generally used in peptide chemistry and the objective compounds can be obtained by removing such protective groups after the respective reactions.
The amino-protective group includes, for example, formyl as well as C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.), phenylcarbonyl, C1-6 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C7-11 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl etc.), trityl, and phthaloyl, each of which may be substituted. The substituent includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, valeryl, etc.), nitro, etc. and the number of substituents may range from 1 to 3.
The carboxyl-protective group includes, for example, C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, and silyl, each of which may be substituted. The substituent includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), formyl, C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butylcarbonyl, etc.), nitro, C1-6 alkyl (e.g. methyl, ethyl, tert-butyl, etc.), and C6-10 aryl (e.g. phenyl, naphthyl, etc.) and the number of substituents may range from 1 to 3.
The hydroxy-protecting group includes, for example, C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C7-11 aralkyl (e.g. benzyl etc.), formyl, C1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.), phenyloxycarbonyl, C7-11 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl etc.), tetrahydropyranyl, tetrahydrofuranyl, and silyl, each of which may be substituted. The substituent includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl (e.g. methyl, ethyl, tert-butyl, etc.), C7-11 aralkyl (e.g. benzyl etc.), C6-10 aryl (e.g. phenyl, naphthyl, etc.), nitro, etc. and the number of substituents may range from 1 to 4.
Such protective groups can be removed by the per se known deprotection methods or any methods analogous thereto. For example, the treatment with an acid, a base, ultraviolet radiation, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, or palladium acetate and reduction can be mentioned by way of example.
In any of the foregoing processes, the desired compound (I) can be synthesized by carrying out any of the known deprotection, acylation, amidation, alkylation, hydrogenation, oxidation, reduction, carbon chain elongation reaction, and substituent exchange reaction or two or more of such reactions in combination as necessary. Those reactions can be typically carried out by the procedures described inter alia in Shin Jikken Kagaku Koza (New Experimental Chemistry Series 14, Vol. 15, 1977 (Maruzen Publishing Co.).
When the objective compound obtainable by the above reaction or reactions is a free compound, it can be converted to a salt in the routine manner. When the product compound is a salt, it can be converted to the free compound or a different salt by the known procedure. The compound (I) thus produced can be isolated and purified from the reaction mixture by the known procedures such as redistribution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and chromatography.
When compound (I) exists as configuration isomers, diastereomers, or conformers, the respective isomers can be optionally isolated by the above-mentioned fractionation and purification procedures. When compound (I) is a racemic compound, it can be resolved into the (S)- and (R)-forms by the conventional optical resolution techniques.
Compound (I) may be a hydrate or an anhydrate.
The compound of the formula: 
wherein Xxe2x80x2 represents SH, OH or NH2; the other symbols have the same meanings as defined above, or a tautomer thereof, or a salt thereof as obtained in the above reaction processes is novel compound and can be used as a starting material for the production of the compound of the present invention.
Among others, the preferred compound include:
Ethyl [(2-mercapto-4,5-dihydronaphtol[1,2-d]thiazol-6-yl)oxy]acetate,
Ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate,
Ethyl [(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)-oxy]acetate, tautomers thereof and salts thereof.
Compound (I) of the invention has a high affinity for the PGI2 receptors with a low toxic potential and a minimal risk of adverse drug reaction and, as such, is of value as a medicine.
Compound (I) of the invention acts as a PGI2 agonist in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, and human) and has platelet aggregation inhibitory, vasodilative, bronchodilative, lipid deposition inhibitory, leukocyte activation inhibitory, and other activities. Thus, compound (I) is useful for the pharmaceutical composition for the prophylaxis and/or treatment of transient ischemic attack (TIA), diabetic neuropathy, peripheral vascular diseases (e.g. peripheral embolism, vibration syndrome, Raynaud""s disease, etc.), systemic lupus erythematosus, post-PTCA reobliteration/restenosis, atherosclerosis, thrombosis (e.g. acute phase of cerebral thrombosis, etc.), diabetic gangrene, hypertension, pulmonary hypertension, ischemic diseases (e.g. cerebral infarction, myocardial infarction, etc.), angina pectoris (e.g. stable angina, unstable angia, etc.), glomerulonephritis, diabetic nephropathy, allergy, bronchial asthma, ulcer, decubitus, coronary restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia during dialysis, etc.
Compound (I) of the invention is a compound of low toxicity and can be safely administered either as it is or in the form of a pharmaceutical composition comprising compound (I) and a pharmacologically acceptable carrier or vehicle, for example in such dosage forms as tablets (including dragees and film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained release tablets or capsules, transdermal drug delivery systems, etc., whether orally or non-orally (e.g. topically, rectally, or intravenously). The content of compound (I) in the pharmaceutical composition of the invention is about 0.01 to 100 weight % based on the total weight of the composition. The dosage is dependent on the background factors, administration route, diagnosis, etc. but when the composition is to be administered orally to an adult human as a pharmaceutical composition for the prophylaxis and/or treatment of transient ischemic attack, about 0.1 to 50 mg/kg body weight, preferably about 0.2 to 30 mg/kg b. wt., more preferably about 0.5 to 10 mg/kg b. wt. as compound (I) can be administered once or in a few divided doses daily.
Compound (I) can be used with other active ingredients such as hypolipidemic (e.g. Pravastatin, etc.), angiotensis II antagonist (e.g. Candesartan Cilexetil, Losartan, etc.), carcium blocker (e.g. Amlodipine, Manidipine, etc.), insulin sensibility activator (e.g. Triglitazone, Pioglitazone, etc.), etc. Compound (I) and said other active ingredient can be formulated into one pharmaceutical composition such as tablets (including dragees and film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained release tablets or capsules, according to per se known methods. They may be separately formulated into different preparations, which may be administered to one and the same subject either simultaneously or at different times.
The pharmacologically acceptable carrier or vehicle which can be used in the manufacture of various dosage forms according to the invention includes those organic and inorganic substances which are conventionally used in pharmaceutical manufacture, such as the excipient, lubricant, binder, and disintegrator for solid dosage forms and the solvent, solubilizer, suspending agent, isotonizing agent, buffer, and local anesthetic for liquid dosage forms. Where necessary, the routine additives such as the antiseptic, antioxidant, coloring agent, sweetener, adsorbent, wetting agent, etc. can be included in the formulation.
The excipient mentioned above includes, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light silicic anhydride.
The lubricant includes, for example, magnesium stearate, calcium stearate, talc, and colloidal silica.
The binder includes, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, gelatin, methylcellulose, and carboxymethylcellulose sodium.
The disintegrator includes, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.
The solvent includes, for example, water for injection, alcohol, propylene glycol, macrogols, sesame oil, corn oil, and olive oil.
The solubilizer includes, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
The suspending agent includes, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc. and hydrophilic macromolecular substances such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
The isotonizing agent includes, for example, glucose, D-sorbitol, sodium chloride, glycerol, and D-mannitol.
The buffer includes, for example, buffer solutions such as, phosphate, acetate, carbonate and citrate.
The local anesthetic includes, for example, benzyl alcohol.
The antiseptic includes, for example, p-hydroxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
The antioxidant includes, for example, salts of sulfurous acid, ascorbic acid, and xcex1-tocopherol.
The following reference examples, examples, formulation example, and experimental examples are intended to describe the present invention in further detail, it being to be understood, however, that these examples are merely illustrative and not defining the scope of the invention and that many changes and modifications may be made by one skilled in the art without departing from the spirit of the invention.
The term xe2x80x9croom temperaturexe2x80x9d as used in the following reference examples and examples generally means a temperature within the range of about 10xc2x0 C. to about 35xc2x0 C. The symbol % stands for weight percent unless otherwise indicated.
The various abbreviations used in the text have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
dd: double doublet
dt: double triplet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
Ph: phenyl
Me: methyl
Et: ethyl
CDCl3: deuterated chloroform
DMSO-d6: deuterated dimethyl sulfoxide
1H-NMR: proton nuclear magnetic resonance spectrum